WO2014195967A2 - Procédé de préparation de pyrroles présentant des activités hypocholestérolémiques hypolipidémiques - Google Patents

Procédé de préparation de pyrroles présentant des activités hypocholestérolémiques hypolipidémiques Download PDF

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Publication number
WO2014195967A2
WO2014195967A2 PCT/IN2014/000367 IN2014000367W WO2014195967A2 WO 2014195967 A2 WO2014195967 A2 WO 2014195967A2 IN 2014000367 W IN2014000367 W IN 2014000367W WO 2014195967 A2 WO2014195967 A2 WO 2014195967A2
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WIPO (PCT)
Prior art keywords
compound
formula
saroglitazar
sodium
base
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PCT/IN2014/000367
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English (en)
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WO2014195967A3 (fr
Inventor
Shriprakash Dhar DWIVEDI
Ramesh Chandra SINGH
Rajendra Gokalbhai CHAVDA
Jagdish Maganlal PATEL
Daya Ram Pal
Jigar Mukundhai RAVAL
Mukul Hariprasad SHARMA
Pranav Jitendra GANGWAR
Sachin Ashokrao PATIL
Vikas PATEL
Vishwadeepak Rama Patil TRIPATHI
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Cadila Healthcare Limited
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Application filed by Cadila Healthcare Limited filed Critical Cadila Healthcare Limited
Priority to US14/894,744 priority Critical patent/US20160107989A1/en
Priority to ES14767148T priority patent/ES2889916T3/es
Priority to MX2015016403A priority patent/MX2015016403A/es
Priority to EP14767148.1A priority patent/EP3004053B1/fr
Publication of WO2014195967A2 publication Critical patent/WO2014195967A2/fr
Publication of WO2014195967A3 publication Critical patent/WO2014195967A3/fr
Priority to ZA2015/08631A priority patent/ZA201508631B/en
Priority to PH12015502667A priority patent/PH12015502667A1/en
Priority to US15/366,229 priority patent/US10435363B2/en
Priority to US16/553,718 priority patent/US20190389797A1/en
Priority to PH12020551628A priority patent/PH12020551628A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/333—Radicals substituted by oxygen or sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/402—1-aryl substituted, e.g. piretanide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/325—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom

Definitions

  • the present invention relates to a process for the preparation of pyrroles having hypolipidemic hypocholesteremic activities.
  • the invention relates to a process for the preparation of saroglitazar and its pharmaceutically acceptable salts, hydrates, solvates, polymorphs or intermediates thereof.
  • the invention also relates to a pharmaceutical composition comprising saroglitazar and its pharmaceutically acceptable salts together with one or more pharmaceutically acceptable carriers, excipients or diluents.
  • Pyrrole derivative of present invention is chemically, (2S)-2-ethoxy-3-[4-(2-(2-methyl- 5-[4-(methylsulfanyl)phenyl]-lH-pyrrol-l-yl)ethoxy)phenyl]propanoic acid, which may be optically active or racemic and its pharmaceutically acceptable salts, hydrates, solvates or polymorphs thereof.
  • the INN name for pyrrole derivative is Saroglitazar ® which is magnesium salt of pyrrole compound of Formula (I), having below chemical structure.
  • the compound of Formula (I) lower or modulate triglyceride levels and/or cholesterol levels and/or lower density lipoproteins (LDL) and raise HDL plasma levels and hence are useful in combating different medical conditions, where such lowering (and raising) is beneficial.
  • LDL lower density lipoproteins
  • the compound of Formula (I) are useful to prevent or reduce the risk of developing atherosclerosis, which leads to diseases and conditions selected from arteriosclerotic cardiovascular diseases, stroke, coronary heart diseases, cerebrovascular diseases, peripheral vessel diseases and related disorders.
  • U.S. Patent No. 6,987,123 B2 discloses novel heterocyclic compounds, their preparation, pharmaceutical compositions containing them and their use in medicine.
  • the US ⁇ 23 patent discloses five reaction pathways for the synthesis of pyrrole derivatives.
  • U.S. PG-Pub. No. 201 1/0275669 Al discloses the process for the preparation of pyrrole derivative of general Formula (1) prepared by the five reaction pathways as disclosed herein above.
  • International (PCT) publication WO 2012/104869 Al provides the use of compound of Formula (1) for the treatment of lipodystrophy.
  • polymorphs affect important pharmaceutical parameters selected from storage, stability, compressibility, density and dissolution rates (important in determining bioavailability). Stability differences may result from changes in chemical reactivity (e.g., differential hydrolysis or oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph), mechanical changes (e. g., tablets crumble on storage as a kinetically favored crystalline form converts to thermodynamically more stable crystalline form) or both (e. g., tablets of one polymorph are more susceptible to breakdown at high humidity). Solubility differences between polymorphs may, in extreme situations, result in transitions to crystalline forms that lack potency or are toxic.
  • chemical reactivity e.g., differential hydrolysis or oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph
  • mechanical changes e. g., tablets crumble on storage as a kinetically favored crystalline form converts to thermodynamically more
  • the physical properties of the crystalline form to that of an amorphous form may be important in pharmaceutical processing.
  • an amorphous form may provide better bioavailability than the crystalline form.
  • a present amorphous form may be useful for formulations which can have better stability, solubility, storage, compressibility etc important for formulation and product manufacturing and doesn't degrade to crystalline forms of saroglitazar.
  • R is selected from mesylate, tosylate, triflate
  • substantially amorphous form of saroglitazar magnesium having particle size distributions having D(10) of about 10 ⁇ or less, D(50) of about 25 ⁇ or less, and D(90) of about 100 ⁇ or less or any combination thereof.
  • saroglitazar magnesium having a purity of at least about 98% by area percentage of HPLC.
  • saroglitazar magnesium having a purity of at least about 99%, more particularly, a purity of at least about 99.5%, further more particularly, a purity of at least about 99.8%, most particularly, a purity of at least about 99.9% by area percentage of HPLC.
  • saroglitazar magnesium having a chiral purity of at least about 98% by area percentage of HPLC.
  • saroglitazar magnesium having a chiral purity of at least about 99%, more particularly, a chiral purity of at least about 99.5%, further more particularly, a chiral purity of at least about 99.8%, most particularly, a chiral purity of at least about 99.9% by area percentage of HPLC.
  • composition comprising an amorphous form of saroglitazar magnesium together with one or more pharmaceutically acceptable carriers, excipients or diluents.
  • FIG. 1 discloses the X-ray diffractogram (XRD) of substantially amorphous form of saroglitazar magnesium of Formula (I);
  • FIG. 2 discloses the X-ray diffractogram (XRD) of hydroxy compound (A);
  • FIG. 3 discloses the X-ray diffractogram (XRD) of mesylate compound (A 1).
  • the process of the present invention which leads to substantially amorphous form of saroglitazar magnesium suitable for pharmaceutical use.
  • the solution prior to any solids formation, can be filtered to remove any undissolved solids, solid impurities prior to removal of the solvent. Any filtration system and filtration techniques known in the art can be used.
  • DMF N,N-dimethylforamide
  • DMAc refers to N,N-dimethylacetamide
  • DMSO refers to ⁇ , ⁇ -dimethylsulfoxide
  • NMP refers to N-methylpyrrolidone
  • THF tetrahydrofuran
  • MTBE refers to methyl tert-butyl ether
  • TAA triethylamine
  • TAA refers to tert-butyl amine
  • DIP A refers to diisopropyl amine
  • DIPEA diisopropyl ethylamine
  • DBU refers to 1 ,8-diazabicyclo[5.4.0]undec-7-ene
  • DABCO refers to l,4-diazabicyclo[2.2.2]octane
  • DBN refers to l ,5-diazabicyclo[4.3.0]non-5-ene
  • HPLC refers to high performance liquid chromatography
  • a substantially amorphous form of saroglitazar magnesium having a purity of at least about 98% by area percentage of HPLC and less than about 0.5% residual solvent.
  • substantially amorphous form of saroglitazar magnesium having an X-ray powder diffraction pattern substantially the same as that shown in FIG.l or by X-ray powder diffraction pattern having characteristic peaks expressed in degress 2 ⁇ ( ⁇ 0.2° 2 ⁇ ) at 4.5°, 7.9° and 9.0° ⁇ 0.2° 2 ⁇ .
  • the substantially amorphous form of saroglitazar magnesium is substantially free from residual solvents.
  • substantially free means residual solvents within the permissible ICH limits suitable for pharmaceutical preparations. For example but not limited to less than about 0.5%, particularly less than about 0.3% or more particularly less than about 0.2% by GC.
  • R is selected from mesylate, tosylate, triflate
  • the organic solvent comprises one or more of alcohols selected from methanol, ethanol, isopropanol, 2-propanol, 1-butanol, and t-butyl alcohol; ketones selected from acetone, butanone, and methyl isobutyl ketone; esters selected from ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; chlorinated hydrocarbons selected from methylene dichloride, ethylene dichloride, and chlorobenzene; hydrocarbons selected from pentane, hexane, heptane, and cyclohexane; ethers selected from tetrahydrofuran, 1 ,4-dioxane, diisopropyl ether, diethyl ether, and methyl ter
  • the base comprises one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, potassium hydride, potassium tert-butoxide, and sodium pentoxide.
  • potassium carbonate may be used.
  • the base may be preferably anhydrous.
  • the phase transfer catalyst comprises one or more of tetrabutyl ammonium bromide (TBAB), tetrabutyl ammonium iodide (TBAI), benzyl triethyl ammonium chloride (TEB AC), polyethylene Glycol (PEG-200, 400, 600, 800, 1000), crown ethers selected from 12-crown-4, 15-crown-5, 18-crown-6, dibenzo-18-crown-6, and diaza-18-crown- 6.
  • the phase transfer catalyst may be 18-crown-6.
  • reaction of hydroxy compound (A) with a mesylate compound (Al) may be performed under heating at 35°C to about reflux temperature of solvents.
  • the reaction may be heated at 75°C to 85°C till the completion of the reaction.
  • the reaction may be heated for about 25 hours to about 40 hours. In particular, for about 36 hours.
  • the obtained alkoxy ester (II) may be proceeded further without isolating. Therefore, the alkoxy ester (II) may be further hydrolyzed in-situ.
  • the base for hydrolyzing alkoxy ester (II) comprises one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, and potassium hydride.
  • sodium hydroxide may be used.
  • the magnesium source comprises one or more of magnesium hydroxide, magnesium methoxide and magnesium acetate.
  • the magnesium source may be magnesium acetate tetrahydrate.
  • the compound of Formula (I) may be obtained by extracting the reaction mixture with one or more organic solvents followed by washing the organic layer and removal of the organic solvents. The residue may be treated with same solvents and added into an anti-solvent to obtain compound of Formula (I).
  • the product thus obtained may be filtered and dried under vacuum tray drier, sieved and milled to obtain particle size distribution. The milled product may be further dried till constant weight may be obtained to obtain saroglitazar magnesium substantially free from residual solvents.
  • the organic solvent used for extraction comprises one or more of esters selected from ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; chlorinated hydrocarbons selected from methylene dichloride, ethylene dichloride, and chlorobenzene; aromatic hydrocarbons selected from toluene, xylene, and ethylbenzene.
  • the anti-solvent comprises one or more of aliphatic hydrocarbons selected from pentane, hexane, heptane, and cyclohexane; ethers like tetrahydrofuran, 1 ,4-dioxane, diisopropyl ether, diethyl ether, and methyl tertbutyl ether.
  • the anti- solvent may be n-heptane.
  • the product may be obtained by removal of anti-solvent by the known technique in the art comprises one or more of filtration, centrifugation, decantation, rotational distillation using device selected from Buchi Rotavapor, spray dyring, agitated thin film drying ("ATFD"), and freeze drying (lyophilization); or any other know techniques.
  • the sieving of product may be done through 0.5 sieve followed by milling. Examples of such milling include various makes of ball mills, roller mills, gyratory mills, multi-mills, Jet-mills.
  • a mill selected from a Micros Super Fine Mill (available from Nara Machinery Co. Ltd or Tokyo, Japan), Multi-Mill Sr. No. G.
  • substantially amorphous form of saroglitazar magnesium having a particle size distribution having D(10) of about 50 ⁇ or less, D(50) of about 200 ⁇ or less and D(90) of about 400 ⁇ ⁇ or less; or any combination thereof.
  • substantially amorphous form of saroglitazar magnesium having a particle size distribution having D(10) of about 10 ⁇ or less, D(50) of about 25 ⁇ or less and D(90) of about 100 ⁇ or less.
  • saroglitazar magnesium having a purity of at least about 98% by area percentage of HPLC.
  • saroglitazar magnesium having a purity of at least about 99%, more particularly, a purity of at least about 99.5%, further more particularly, a purity of at least about 99.8%, most particularly, a purity of at least about 99.9% by area percentage of HPLC.
  • saroglitazar magnesium having a chiral purity of at least about 98%) by area percentage of HPLC.
  • saroglitazar magnesium having a chiral purity of at least about 99%>, more particularly, a chiral purity of at least about 99.5%, further more particularly, a chiral purity of at least about 99.8%), most particularly, a chiral purity of at least about 99.9% by area percentage of HPLC.
  • a process for the preparation of hydroxy compound of Formula (A) is provided.
  • the base in step (a) comprises one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, and potassium hydride.
  • aqueous sodium hydroxide solution may be used.
  • the reaction mixture comprising L-tyrosine, cupric sulphate pentahydrate and aqueous sodium hydroxide may be heated from about 40°C to reflux temperature of water.
  • the reaction mixture may be heated at about 100°C to about 102°C for about 1 hour and cooled to about 20°C to about 25°C.
  • the reaction mixture may be further diluted with one or more of organic solvents.
  • the organic solvent comprises one or more of alcohols selected from methanol, ethanol, isopropanol, 2-propanol, 1-butanol, and t-butyl alcohol; ketones selected from acetone, butanone, and methyl isobutyl ketone; esters selected from ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate.
  • methanol may be used.
  • the copper complex of L-tyrosine solution may be treated with benzyl halide in the presence of a base.
  • the base comprises same or different from the one used herein before.
  • sodium hydroxide may be used.
  • the benzyl halide comprises one or more of benzyl chloride or benzyl bromide. In particular, benzyl bromide may be used.
  • the reaction mixture may be further heated from about 40°C to about reflux temperature of solvent.
  • the reaction mixture may be heated from about 60°C to about 65°C.
  • the benzyl protected L-tyrosine copper complex may be isolated by the known methods as described herein above.
  • the complex may be hydrolyzed with an acid to obtain compound (D).
  • the acid comprises one or more of acetic acid, hydrochloric acid, sulfuric acid, formic acid, hydrobromic acid, and trifluoroacetic acid.
  • hydrochloric acid may be used.
  • the compound (D) obtained in step (b) may be diazotized with sodium nitrite in presence of an acid.
  • the acid comprises one or more of hydrochloric acid, sulfuric acid, hydrobromic acid, and nitric acid.
  • sulfuric acid may be used.
  • the diazotization may be performed in organic solvents comprises one or more of alcohols selected from methanol, ethanol, isopropanol, 2-propanol, 1-butanol, and t- butyl alcohol; ketones selected from acetone, butanone, and methylisobutyl ketone; esters selected from ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; polar aprotic solvents selected from ⁇ , ⁇ -dimethylforamide, N,N- dimethylacetamide, N-methylpyrrolidone, and ⁇ , ⁇ -dimethylsulfoxide; or mixtures thereof.
  • N,N-dimethylsulfoxide may be used.
  • the compound (C) may be obtained by usual work-up procedure in one or more organic solvents or mixture thereof.
  • the organic solvent comprises mixture of ethyl acetate and water.
  • the organic solvent for step (d) comprises one or more of esters selected from ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; hydrocarbons selected from toluene, xylene, ethyl benzene, heptane, hexane, and cyclohexane; chlorinated solvents selected from methylene dichloride, ethylene dichloride, chlorobenzene, chloroform, and carbontetrachloride. In particular, toluene may be used.
  • the compound (C) may be reacted with diethyl sulfate in the presence of a base and a phase transfer catalyst.
  • the base comprises one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, and potassium hydride.
  • potassium hydroxide may be used.
  • the phase transfer catalyst comprises one or more of tetrabutyl ammonium bromide (TBAB), tetrabutyl ammonium iodide (TBAI), benzyl triethyl ammonium chloride (TEBAC), polyethylene Glycol (PEG-200, 400, 600, 800, 1000), crown ethers selected from 12-crown-4, 15-crown-5, 18-crown-6, dibenzo-18-crown-6, and diaza-18-crown- 6.
  • the phase transfer catalyst may be TBAB.
  • the process embodiment involves partitioning the reaction mixture after completion of the reaction by water.
  • the toluene layer may be distilled under vacuum and degassed.
  • the residue may be further distilled to remove excess diethyl sulfate and treated with alcohols selected from methanol, ethanol, isopropanol, and butanol. In particular, ethanol may be used.
  • the ethanolic solution of residue may be characoalized and filtered.
  • the filtrate may be treated with triethylamine at reflux temperature from about 75°C to 85°C followed by removal of ethanol and treating with ethyl acetate.
  • the compound (B) may be obtained in form of oil and may be preceded further. In general, the compound (B) may be deprotected i.e.
  • the catalyst for debenzylation comprises one or more of Pd/C, Raney Nickel, Vitride, and L1AIH 4 .
  • Pd/C may be used for debenzylation under autoclave conditions.
  • the hydroxy compound (A) may be obtained by usual work-up procedure involving use organic solvents.
  • the organic solvent comprises one or more of alcohols selected from methanol, ethanol, isopropanol, 2-propanol, 1 -butanol, and t- butyl alcohol; ketones selected from acetone, butanone, and methyl isobutyl ketone; esters selected from ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate, chlorinated hydrocarbons selected from methylene dichloride, ethylene dichloride, and chlorobenzene, aromatic hydrocarbons selected from toluene, xylene, and ethylbenzene; aliphatic hydrocarbons selected from pentane, hexane, heptane, and cyclohexane; ethers selected from tetrahydrofuran, 1,4-dioxane, diisopropyl ether, diethylether, and methyl tert-tert-
  • the mixture of diisopropyl ether and n-heptane may be used.
  • the hydroxy compound (A) obtained is crystalline characterized by X-ray powder diffraction.
  • the crystalline hydroxy compound (A) is having an X-ray powder diffraction having characteristic peaks expressed in degrees 2 ⁇ ( ⁇ 0.2° 2 ⁇ ) at about 7.0, 13.4, 13.9, 14.6, 15.3, 16.6, 19.0, 21.7, 22.1, 23.5, 24.4, 26.1, 26.8 and 29.5 ⁇ 0.2° 2 ⁇ .
  • the organic solvent comprises one or more of esters selected from ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; hydrocarbons selected from toluene, xylene, ethyl benzene, heptane, hexane, and cyclohexane; chlorinated solvents selected from methylene dichloride, ethylene dichloride, chlorobenzene, chloroform, and carbontetrachloride.
  • esters selected from ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate
  • hydrocarbons selected from toluene, xylene, ethyl benzene, heptane, hexane, and cyclohexane
  • chlorinated solvents selected from methylene dichloride, ethylene dichloride, chlorobenzene
  • the base in step (a) comprises one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydride, sodium methoxide, potassium tert-butoxide, and sodium pentoxide.
  • sodium methoxide may be used.
  • the embodiments of the process may further include in-situ hydrolyzing the compound (Dl) without isolating from step (a) as the scope of the invention.
  • the compound (Dl) may be hydro lyzed with same or different base as disclosed herein above.
  • the base for hydrolysis comprises one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydride, sodium methoxide, potassium tert-butoxide, and sodium pentoxide. More particularly, sodium hydroxide may be used.
  • the reaction mixture may be preferably diluted with one or more of other organic solvents.
  • the other organic solvent comprises one or more of alcohols selected from methanol, ethanol, isopropanol, 2-propanol, 1-butanol, and t-butyl alcohol; ketones selected from acetone, butanone, and methylisobutyl ketone; esters selected from ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate.
  • methanol may be used.
  • the compound (CI) may be obtained by decarboxylation of carboxylic acid derivative obtained in-situ which may not be isolated.
  • the compound (B l) may be obtained by treating the diketo compound (Cl) with ethanolamine under Paal-Knorr conditions in the presence of an acid.
  • the acid comprises one or more of acetic acid, hydrochloric acid, sulfuric acid, formic acid, hydrobromic acid, trifluoroacetic acid, and pivalic acid.
  • pivalic acid may be used.
  • the compound (Bl) may be proceeded for further reaction in-situ.
  • the compound (Bl) obtained in step (c) may be reacted with methane sulphonyl chloride in toluene in the presence of a base.
  • the base for step (d) comprises one or more of inorganic bases selected from sodium hydroxide, potassium hydroxide, lithium hydroxide; sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate; and ammonia or its aqueous solution; and organic bases selected from methyl amine, ethyl amine, TEA, TBA, DIPA, DIPEA, pyridine, piperidine, morpholine, DBU, DABCO or DBN.
  • inorganic bases selected from sodium hydroxide, potassium hydroxide, lithium hydroxide
  • sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate sodium bicarbonate
  • ammonia or its aqueous solution and organic bases selected from methyl amine, ethyl amine, TEA, TBA, DIPA, DIPEA, pyridine, piperidine, morpholine, DBU, DABCO or DBN.
  • organic bases selected from methyl amine, ethyl amine, TEA, T
  • the compound (Al) may be isolated by removal of toluene by distillation followed by treating the residue with methanol and removal of methanol to obtain wet-cake.
  • the wet product may be dried in vacuum tray dryer to obtain crystalline mesylate compound of Formula ( A 1 ) .
  • the crystalline mesylate compound (Al) is having an X-ray powder diffraction having characteristic peaks expressed in degress 20 ( ⁇ 0.2° 2 ⁇ ) at about 12,4, 15.0, 17.7 and 23.2 ⁇ 0.2° 20.
  • Powder X-ray Diffraction of saroglitazar magnesium can be obtained under following conditions.
  • Powder X-ray Diffraction X-ray powder diffraction spectrum was observed on a MF 2100 2KW X-ray Powder diffractometer of make Rigaku having a Copper Ka-radiation at a voltage of 40kV and 30mA. Approximately 150 mg sample was gently flattened on a quartz plate without further processing (e.g. Grinding and sieving) and scanned from 4° to 40° at 0.010° sampling width and 4.000° per minute. Any other X-ray powder diffractometer of similar conditions may also be used.
  • saroglitazar magnesium alongwith its intermediates may be prepared by the reaction scheme- 1, scheme-2 and scheme-3 as shown below, which is also the scope of the present invention.
  • R represents suitable hydroxy leaving group like mesylate, tosylate and triflate group.
  • compositions comprising saroglitazar of the invention.
  • pharmaceutical compositions includes pharmaceutical formulations comprises one or more of tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, and injection preparations.
  • compositions containing the saroglitazar of the invention may be prepared by using diluents or excipients selected from fillers, bulking agents, binders, wetting agents, disintegrating agents, surface active agents, and lubricants.
  • compositions of the invention can be selected depending on the therapeutic purpose, for example tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
  • a pharmaceutical composition comprising substantially amorphous form of saroglitazar magnesium having a particle size distribution having D(10) of about 10 ⁇ or less, D(50) of about 25 ⁇ or less and D(90) of about 100 ⁇ or less together with one or more pharmaceutically acceptable carriers, excipients or diluents.
  • a pharmaceutical composition comprising substantially amorphous form of saroglitazar magnesium together with one or more pharmaceutically acceptable carriers, excipients or diluents.
  • the reaction mixture was heated to 60°C-65°C and maintained for 4 hours and cooled to 20° to 30°C.
  • the reaction mixture was filtered and washed with water-methanol mixture (1 :2) and dried for 30 min.
  • the wet-cake was treated with HCl solution (162.0 ml) in water (944 ml) and resulting reaction mixture was cooled to 15° to 20°C and stirred for 30 min.
  • the reaction mixture was filtered and washed with water.
  • the wet-cake was treated with aqueous liquor ammonia solution (1 105 ml) and stirred for 1 hour.
  • the product was filtered and washed with water and dried to obtain 1 10 g of compound (D).
  • the separated aqueous layer was treated with 200 ml of ethyl acetate 500 ml of water.
  • the organic layer was treated with 10% sodium chloride solution and allowed to settle.
  • the organic layer was separated and charcoalized and dried over sodium sulfate.
  • the reaction mixture was filtered and washed with 100 ml of ethyl acetate.
  • the filtrate was distilled and residue was treated with 5ml of DMSO.
  • the reaction mixture was heated to 60° to 65°C and cooled to 5° to 10°C and filtered.
  • the product was washed with ethyl acetate and dried in hot air oven for 12 hours at 50° to 55°C.
  • the diethyl sulfate was distilled out under high vacuum at 65° to 76°C and the residue was diluted with 837 ml of ethanol and charcoalized and filtered. The bed was washed with ethanol 279 ml, and filtrated. The filtrated was added triethylamine (69.55 g) and heated to reflux for 6 hr and cooled to 60° to 65°C. The reaction mixture was again charcoalized cooled atmospherically to 25° to 30°C, filtered and washed with ethanol. The ethanol was distilled out under vacuum completely and the residue was cooled to 25° to 30°C. Ethyl acetate (1000 ml) and water (1000 ml) were added and reaction mixture was stirred for 30 min.
  • the separated ethyl acetate layer was washed with NaHC0 3 solution (400 ml) and water 1000 ml.
  • the ethyl acetate layer was washed with sodium chloride solution and dried over anhydrous sodium sulphate and characoalized.
  • the reaction mixture was filtered and washed with ethyl acetate. The filtrate was collected and oil residue was obtained.
  • reaction mixture was filtered and pivalic acid (57.3 g) and ethanol amine (143.9 g) were added and heated to 105° to 1 15°C for removing water azeotropically.
  • the toluene layer was separated and tri ethyl amine (271.85 g) was added at 25° to 35°C and the reaction mixture was cooled to 10° to 20°C.
  • Methane sulphonyl chloride 282.5 g was added dropwise, and stirred for 2 hours and heated to 35° to 45°C.
  • the reaction mixture was filtered and washed with toluene.
  • the reaction mixture was cooled to 25° to 35°C and water (1000.0 ml) was added and stirred for 15 min.
  • the separated aqueous layer was treated with cyclohexane (200.0 ml) and stirred for 15 min.
  • the organic layers were combined and washed with caustic solution (600.0 ml).
  • the separated organic layer was washed with water (600.0 ml) and characoalized with (5.0 g) charcoal and stirred for 30 min and filtered.
  • the filtrate was distilled to remove cyclohexane and the residue was collected.
  • the residue as obtained was treated with ethanol (400.0 ml) and stirred for 15 min.
  • Sodium hydroxide 20.14 g solution in water (200.0 ml) was added and the reaction mixture was stirred for 3 hours.
  • the reaction mixture was diluted with water (1800.0 ml) and stirred for 15 min.
  • the separated aqueous layer was washed with n-butyl acetate.
  • the separated aqueous layer was added magnesium acetate tetrahydrate solution (90.0 g) in water (100.0 ml) and stirred for 1 hour.
  • the aqueous layer was extracted with methylene dichloride (200 ml).
  • the separated organic layer was washed with sodium chloride solution and charcoalized.
  • the charcoalized solution was filtered and filtrate was distilled to remove methylene dichloride completely.
  • the residue was diluted with methylene dichloride (1000 ml) and stirred for 30 min.
  • the organic solution was added into n-heptane (1500 mL) and stirred for 3 hours.
  • the product was filtered and washed with n-heptane and dried in vacuum tray dryer at 25°C to 30°C for 3 hours.
  • the product was sieved through 0.5 mm sieve and milled through jet-milled.
  • the product was further dried in vacuum tray drier at 40°C to 50°C for 6 hours followed by drying at 55°C to 65°C for 40 hours to obtain substantially amorphous form of saroglitazar magnesium (I).
  • the compound is characterized by X-ray power diffraction (FIG.l). Purity > 98% by area percentage of HPLC, Chiral Purity > 99% by area percentage of HPLC.
  • Residual solvents Cyclohexane ⁇ 0.3%, Tetrahydrofuran ⁇ 0.07%, ethanol ⁇ 0.3%, n- butyl. acetate ⁇ 0.5%, methylene dichloride ⁇ 0.06% and n-heptane ⁇ 0.5% by GC.
  • Procedure for preparation of saroglitazar dosage form comprises;
  • the active ingredient (Saroglitazar magnesium) with pharmaceutically acceptable carriers, excipients or diluents selected from microcrystalline cellulose, lactose, magnesium oxide, povidone, talc, magnesium stearate, croscarmellose sodium and colloidal silicon dioxide.

Abstract

La présente invention concerne pyrroles présentant des activités hypocholestérolémiques hypolipidémiques. L'invention concerne le saroglitazar et ses sels, hydrates, solvates, polymorphes ou intermédiaires pharmaceutiquement acceptables. La présente invention concerne également un procédé de préparation du saroglitazar. En outre, l'invention concerne les intermédiaires du saroglitazar, ainsi qu'un procédé de préparation de ceux-ci.
PCT/IN2014/000367 2013-05-30 2014-05-30 Procédé de préparation de pyrroles présentant des activités hypocholestérolémiques hypolipidémiques WO2014195967A2 (fr)

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US14/894,744 US20160107989A1 (en) 2013-05-30 2014-05-30 A process for preparation of pyrroles having hypolipidemic hypocholesteremic activities
ES14767148T ES2889916T3 (es) 2013-05-30 2014-05-30 Un procedimiento para la preparación de pirroles con actividades hipolipidémicas e hipocolesterémicas
MX2015016403A MX2015016403A (es) 2013-05-30 2014-05-30 Proceso para la preparacion de pirroles que tienen actividad hipolipidemica e hipocolesterolemica.
EP14767148.1A EP3004053B1 (fr) 2013-05-30 2014-05-30 Procédé de préparation de pyrroles présentant des activités hypocholestérolémiques hypolipidémiques
ZA2015/08631A ZA201508631B (en) 2013-05-30 2015-11-23 A process for preparation of pyrroles having hypolipidemic hypocholesteremic activities
PH12015502667A PH12015502667A1 (en) 2013-05-30 2015-11-27 A process for preparation of pyrroles having hypolipidemic hypocholesteremic activities
US15/366,229 US10435363B2 (en) 2013-05-30 2016-12-01 Process for preparation of pyrroles having hypolipidemic hypocholesteremic activities
US16/553,718 US20190389797A1 (en) 2013-05-30 2019-08-28 Process for preparation of pyrroles having hypolipidemic hypocholesteremic activities
PH12020551628A PH12020551628A1 (en) 2013-05-30 2020-10-02 A process for preparation of pyrroles having hypolipidemic hypocholesteremic activities

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